Liver cirrhosis is a major cause of morbidity and mortality in Veterans, primarily due to complications such as ascites and hepatic encephalopathy (HE). HE is linked with a systemic pro-inflammatory milieu propagated by an impaired intestinal barrier and gut dysbiosis. Despite maximal therapy (lactulose/rifaximin), a significant proportion of Veterans have HE that continues to recur, which is a major burden on their caregivers and VHA system. We have recently published a small randomized trial of fecal microbial transplantation (FMT), in this population, which was safe and prevented total and HE-related hospitalizations. This was associated with favorable bile acid (BA) and microbial changes which lasted for >1 year with one FMT. A similar small oral capsule FMT trial is underway at our center with good safety signals. There is also evidence in non-cirrhotic FMT studies that microbe-free portions can be as effective as full FMT. However, the mechanism of action of FMT in cirrhosis is needs further investigation. We hypothesize that ?Fecal microbial transplant delivered from the combined oral and rectal route is safe, well- tolerated and associated with lower hospitalizations, improved modulation of gut microbial composition and functionality and brain function in patients with hepatic encephalopathy compared to those treated with FMT from either routes alone or with placebo; this improvement is mediated by microbial products?. We will test this hypothesis using two translational aims Aim 1: To determine the effect of dual oral and rectal administration of FMT from a rational donor on clinical outcomes (hospitalizations, brain function, quality of life) and host-microbiota interactions (microbial composition and bile acid composition with systemic and intestinal inflammation), compared to single route of administration and placebo, in cirrhotic patients with HE using a randomized, phase II clinical trial. Outpatients with recurrent HE (n=100) will be randomized into four groups (Group 1: Dual oral and rectal FMT, Group 2: Oral FMT and rectal placebo, Group 3: Oral placebo and Rectal FMT and Group 4: Oral and rectal placebo) and followed for 6 months under an FDA IND double-blind clinical trial. FMT donors will be selected using machine learning on the basis of beneficial taxa from OpenBiome donors (collaborator), which will be used for all FMT-assigned subjects. The primary outcome is all-cause hospitalizations. Patients will undergo baseline evaluation for cirrhosis severity, brain function, intestinal permeability along with collection of serum and stool and fecal bile acid profile analysis. Patients will be followed till 6 months for outcomes. We will define the effect of FMT on systemic inflammation, intestinal permeability, bile acid profile, and its linkage with microbial composition and clinical outcomes between groups. Aim 2: To determine the effect of human FMT on neuro-inflammation and gut microbial function using germ-free mice and conventional cirrhotic mice with microbe-rich and microbe-free (sterile) supernatants from the FMT donors. It is not clear which components of the FMT material, the microbes or their products such as bile acids, mediate its effects. Entire and microbe-free supernatants generated from pooled FMT donor samples, recipients? baseline samples and post-FMT samples, will be used to humanize GF mice. In addition, conventional cirrhotic mice will receive healthy donor material using the same protocol. Differences in neuro-inflammation will be studied between conventional cirrhotic and GF mice after colonization and between those colonized with entire samples and with only microbial products. A specific change in intestinal bile acid profile as a mediator of these changes will be investigated. The team has been working cohesively with expertise in clinical and translational cirrhosis research in Veterans. These results will set the foundation for future trials determining the role of FMT in liver disease and help define better donor-patient matches from a microbial perspective in this underserved population.